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    A specific inhibitor of polo-like kinase 1, GSK461364A, suppresses proliferation of Raji Burkitt's lymphoma cells through mediating cell cycle arrest, DNA damage, and apoptosis
    (Elsevier Ireland Ltd, 2020) Ergul, Mustafa; Bakar-Ates, Filiz
    Polo-like kinase 1 (PLK1) is a prominent mediatory player during the cell cycle, mitosis, and cytokinesis in eukaryotic cells. Besides its physiological roles, PLK1 expression is upregulated in a wide range of human malignant tumors and its overexpression worsens prognosis, therefore, specific inhibition of PLK1 in tumor cells is a fascinating approach for the development of novel chemotherapeutics. The present study elucidated the potential cytotoxic effects of a PLK1 inhibitor, GSK461364A, in five cancer cell lines including Raji, K562, PC3, MCF-7, MDA-MB-231, along with noncancerous L929 cells by XTT assay. The cells were treated for 24 h with GSK461364A at different concentrations ranged between 0.5 and 40 mu M and significant cytotoxicity was observed in all treated groups with the IC50 values between 2.36 and 4.08 mu M. GSK461364A was also found to be safer with lower cytotoxicity against L929 cells and the IC50 value was found to be greater than 40 mu M. Raji cells were identified as the most sensitive cell line against GSK461364A with the lowest IC50 values, hence it was selected for further studies to evaluate the underlying mechanism of cytotoxic activity. The treatment of Raji cells with GSK461364A caused a cell cycle arrest at the G2/M phase, also altered TOS, which is an indicator of oxidative stress, and DNA damage response, significantly. The Annexin V binding assay revealed that GSK461364A treatment significantly increased in the percentage of early and late apoptotic cells. Fluorescence imaging also showed that GSK461364A treatment significantly induced apoptosis of Raji cells. The apoptotic effect of the compound has also been confirmed by increased expressions of Bax and cleaved caspase 3 and along with the decreased expression of BCL-2. The results demonstrated that GSK461364A induced anticancer effects which was mainly promoted by cell cycle arrest, oxidative stress, DNA damage, and finally apoptosis in Burkitt's lymphoma cells. Taken together, the present results emphasized that GSK461364A could be a useful therapeutic agent in patients with Burkitt's lymphoma. However, further studies are required to consolidate the anticancer activity of this promising compound.
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    Investigation of molecular mechanisms underlying the antiproliferative effects of colchicine against PC3 prostate cancer cells
    (Pergamon-Elsevier Science Ltd, 2021) Ergul, Mustafa; Bakar-Ates, Filiz
    This work examined the cytotoxic effects of colchicine on PC3 cells and elucidated the possible underlying mechanisms of its cytotoxicity. The cells were exposed to colchicine at different concentrations ranging from 1 to 100 ng/mL for 24 h, and it showed considerable cytotoxicity with an IC50 value of 22.99 ng/mL. Mechanistic studies also exhibited that colchicine treatment results in cell cycle arrest at the G2/M phase as well as decreased mitochondrial membrane potential and increased early and late apoptotic cells. The apoptotic and DNAdamaging effects of colchicine have also been verified by fluorescence imaging and ELISA experiments, and they revealed that while colchicine treatment significantly modulated expression as increases in Bax, cleaved caspase 3, cleaved PARP, and 8-hydroxy-desoxyguanosine levels and as a decrease of BCL-2 protein expression. Besides, colchicine treatment significantly increased the total oxidant (TOS) level, which is a signal of oxidative stress and potential cause of DNA damage. Finally, the results of quantitative real-time PCR experiments demonstrated that colchicine treatment concentration-dependently suppressed MMP-9 mRNA expression. Overall, colchicine provides meaningful cytotoxicity on PC3 cells due to induced oxidative stress, reduced mitochondrial membrane potential, increased DNA damage, and finally increased apoptosis in PC3 cells. Nevertheless, further research needs to be conducted to assess the potential of colchicine as an anticancer drug for the treatment of prostate cancer.
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    Novel indole hydrazide derivatives: Synthesis and their antiproliferative activities through inducing apoptosis and DNA damage
    (Wiley-V C H Verlag Gmbh, 2020) Kilic-Kurt, Zuhal; Acar, Cemre; Ergul, Mustafa; Bakar-Ates, Filiz; Altuntas, Tunca G.
    A series of novel indole hydrazide derivatives was synthesized and evaluated for their anticancer activities. Compound 12 exhibited the highest antiproliferative activity against the MCF-7 cell line, with an IC50 value of 3.01 mu M. Treatment of MCF-7 cells with compound 12 led to cell cycle arrest at the G0/G1 phase and also displayed a significant annexin V binding pattern, indicating that compound 12 is effective in apoptotic cell death. The Western blot analysis showed that compound 12 increased the expression of proapoptotic Bax and decreased the levels of the antiapoptotic Bcl-2 protein. It was also observed that MCF-7 cells treated with compound 12 showed reduced levels of procaspase-3 and -9 proteins. Moreover, compound 12 treatment induced a significant DNA damage in MCF-7 cells by increasing H2AX and ATM phosphorylation.
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    RO3280: A Novel PLK1 Inhibitor, Suppressed the Proliferation of MCF-7 Breast Cancer Cells Through the Induction of Cell Cycle Arrest at G2/M Point
    (Bentham Science Publ Ltd, 2019) Ergul, Mustafa; Bakar-Ates, Filiz
    Background: As a member of serine/threonine-protein kinase, Polo-like kinase 1 (PLK1) plays crucial roles during mitosis and also contributes to DNA damage response and repair. PLK1 is aberrantly expressed in many types of tumor cells and increased levels of PLK1 are closely related to tumorigenesis and poor clinical outcomes. Therefore, PLK1 is accepted as one of the potential targets for the discovery of novel anticancer agents. The objective of this study was to assess the cytotoxic effects of a novel PLK1 inhibitor, RO3280, against MCF-7, human breast cancer cells; HepG2, human hepatocellular carcinoma cells; and PC3, human prostate cancer cells, as well as non-cancerous L929 fibroblast cells. Methods: Antiproliferative activity of RO3280 was examined using the XTT assay. Flow cytometry assay was performed to evaluate cell cycle distribution, apoptosis, multicaspase activity, mitochondria' membrane potential, and DNA damage response. Apoptosis with fluorescence imaging studies was also examined. Results: According to the results of .XTT assay, although RO3280 displayed potent cytotoxicity in all treated cancer cells, the most sensitive cell line was identified as MCF-7 cells that were selected for further studies. The compound induced a cell cycle arrest in MCF-7 cells at G2/M phase and significantly induced apoptosis, multicaspase activity, DNA damage response, and decreased mitochondria' membrane potential of MCF-7 cells. Conclusion: Overall, RO3280 induces anticancer effects promoted mainly by DNA damage, cell cycle arrest, and apoptosis in breast cancer cells. Further studies are needed to assess its usability as an anticancer agent with specific cancer types.